Hormone composition for improving meat production efficiency and method for using same



United States Patent 9 HQRMONE (IGMPQSITEUN FOR IMPROVING MEATPRODUCTION EFFICIENCY AND METHGD FOR USING SAME William Earl Matter andFrank C. Moore, Indianapolis, Ind, assignors to Matter and Moore, Inc.,Indianapolis, Ind, a corporation of Indiana No Drawing. ApplicationJanuary 14, 1954 Serial No. 404,133

7 Claims. (Cl. 167-53.1)

This invention relates to the improvement of meat production efliciencyin meat producing animals such as fowl, beef and sheep.

The meat producer, growing meat producing animals for sale as meat, isconcerned with a number of factors. He is concerned with quantity, thatis, with the dressed weight of meat produced by the animals. He isconcerned with quality, that is, that the meat produced is of high gradeand will command a premium price on the market, which involves theappearance of the dressed meat, its tenderness, and its palatability. Heis also concerned with production efficiency, that is, with producinggood quantities of high quality meat in a minimum of time, with aminimum of labor, and at low cost. This involves the factor of feedconversion or feed utilization, that is, the rate of meat gain per unitof feed consumed. It also involves the factor of obtaining the desiredfinish" on the animal, which depends on the final stages of feeding andhandling, and largely determines the quality rating of the meatproduced. A properly finished animal attains what is referred to as acertain bloom, and its meat has an appearance which in beef is referredto as marbling and which results from the deposition of fat between thefibers of the meat. When chemical compositions are used to stimulate orexpedite the desired meat production, it is of course essential that thecompositions used be non-toxic to the animal and do not impede thedesired development of the animal and thus do not by their side effectsdestroy the desired result. Such compositions must also produce nodeleterious change in the meat of the animal and must neither leave norproduce a residue in the meat which may be toxic or harmful to consumersof the meat.

It is the primary object of this invention to improve themeat producingprocess and the resulting meat product, and thus to provide individualand combined improvements in the several factors referred to above.

It is known that certain improvements in certain of these factors may beobtained by administering to the animal at a calculated time prior toits butchering a quantity of an estrogen, such as diethylstilbestrol, orother lipogenic agent. For example, diethylstilbestrol has commonly beenadministered to chickens and other fowl approximately three to fiveweeks prior to their marketing. This has been done by implanting apellet containing the diethylstilbestrol subcutaneously high up on theneck of. the chicken. It has also been done by the forced extrusioninjection at substantially that same site of a plastic semi-solidmaterial containing the diethylstilbestrol, in accordance with a processand using a product invented by us, as disclosed in our co-pendingapplication Serial No. 193,195, filed October 31, 1950, now Patent No.2,681,297.

We have now discovered that meat production is improved by injectionadministration of a thyroid-depressing agent; and that especiallyimproved results are obtained by administering to the animal at asuitable time in advance of-its butchering both (a) a lipo'genic agentand ice (b) a thyroid-depressing agent, preferably by administeringthese two agents together in a composition in combination with (c) asuitable vehicle, especially by administering such a composition beneaththe skin, by the forcedextrusion injection procedure and with a plasticsemisolid extrudable composition of the physical character disclosed inour aforesaid co-pending application.

The lipogenic agent used may be any of a number of chemical compounds,natural or synthetic, or combinations of such compounds, which have alipogenic function. These include especially the various estrogenicmaterials, both natural and synthetic, of which a number are known. Ofsuch estrogenic materials, we prefer to use diethylstilbestrol, for muchinformation is knownwith respect to its physiological action, itseffectiveness for the purpose, and its low toxicity, and it isrelatively low in cost and readily available in pure crystalline form.Preferably, the lipogenic agent used should be relativelywater-insoluble, which is a characteristic of diethylstilbestrol, sothat it may be administered through the skin, for example,subcutaneously or intramuscularly, and will form a deposit in solid orcrystalline state from which it will be slowly absorbed and utilized bythe animal to produce a long-acting effect.

The thyroid-depressing agent used may be any of a number of chemicalcompounds which have a thyroiddepressing effect or which reduce theamount of thyroxin present in the animal system during the period of itseffect. Such thyroid-depressing agents include, for ex ample, thiouraciland its various anti-thyroid derivatives such as propylthiouracil, thevarious anti-thyroid thiocyanate compounds, and the anti-thyroidimidazole compounds. Of these, we prefer to usel-methyl-Z-mercaptoimidazole, commonly known as methimazole and available on the market as tapazole, because of its high degree ofeffectiveness, the small dosage required, its high margin of safety fromthe point of view of toxicity, and its relatively low cost and readyavailability.

The lipogenic agent and thyroid-depressing agent are preferablyadministered together in a composition corp taining both agents in aco-operating vehicle. The vehicle is desirably one which forms acomposition adapted to be administered through the skin of the animal tocarry the agents into the animal, and preferably one which Will causethe formation of a deposit from which one or both of the active agentswill be absorbed slowly to produce a long'acting elfect throughout thedesired period prior to butchering.

Solid compositions might be used, but these would require a pelletimplantation procedure, which is difficult and slow, and variable in itsresults. Liquid injectable compositions might be used, but these involveditliculties' of maintaining a relatively water-soluble agent suchasdiethylstilbestrol in uniform distribution, and difiiculties ofadministering a liquid containing suspended solids.

Most desirably, We prefer a composition in plastic semi-solid statewhich is administrable by forced extrusion injection, as set forth inour aforesaid co-pending application.

The preferred composition is one containing the lipogenic andthyroid-depressing agents in uniform distribu tion (suspended ordissolved) in a water-soluble vehicle. In physical state at the bodytemperature of the animal and at lower temperatures, the composition isdesirably semi-solid and non-flowing, but with sufiicient plasticity tobe extrudable under elevated pressures through a hypodermic needle ofreasonable size, for example, extrudable at a pressure of 200 to 500pounds per square inch through a No. 16 hypodermic needle. The stiffphysical state of the composition will maintain the uniform distributionof the active agents, and will facilitate economical and speedyadministration. It is preferably administered example, the chicken bodytemperature of 107 F. The.

plasticizer used may be any of a number of liquids which are misciblewith the polyethylene glycol and are known to have plasticizing effectsin combination with it. Suitable plasticizers include polyhydricalcohols, such as glycerin, propylene glycol, and preferablypolyethylene glycols of low molecular weight and of normal liquid state,such as the polyethylene glycols having an averag molecular weight ofthe order of 200 to 300.

.A vehicle including a polyethylene glycol wax and a plasticizerdesirably contains from 30% to 70% (by weight) of a polyethylene glycolwax having an average molecular weight of 4000 or higher, and from 70%to 30% of the plasticizer such as polyethylene glycol liquid having anaverage molecular weight of 200, and most desirably contains from 40% to60% of the polyethylene glycol and from 60% to 40% of the plasticizer.

A composition in accordance with our invention may be prepared by mixingthe active agents and the vehicle in any suitable way. Preferably, inmaking a plastic semi-solid composition, the vehicle may be melted, asat a temperature of about 85 F., the water insoluble estrogen and thethyroid-depressing agent are added to the hot mixture, and the resultingmixture is stirred to thoroughly distribute the active agents throughoutthe mixture, The hot mixture is then brought to room temperature, atwhich it takes on the desired physical state of a plastic semi-solidpaste-like mass. The semi-solid consistency of the composition willretain a high concentration of the active ingredients and maintain theuniform distribution thereof throughout the composition during storage,distribution, and use. The desired dosage may therefore be contained ina relatively small quantity of the composition.

The amounts and relative proportions of the lipogenic agent and thethyroid-depressing agent may vary, depending upon their relativeactivity per unit quantity. In prior administrations ofdiethylstilbestrol alone to fowl and cattle for meat growth promotingeffects, we have found it desirable to use a plastic semi-solidcomposition containing the diethylstilbestrol in a concentration ofabout 60 to 75 mg. of diethylstilbestrol per cc. of total composition sothat 15 mg. of diethylstilbestrol is administered by an injection of 0.2to 0.25 cc. of total composition, and this is the normal dose inchickens. In the present composition, we may use that same proportion ofdiethylstilbestrol, or its equivalent of other lipogenic agent, per cc.of the composition. In combination with the thyroid-depressing agent,however, we may use a somewhat lower dosage of lipogenic agent. Thus, inchickens, we desirably use from 5 mg. to 15 mg., and preferably about 10mg. of diethylstilbestrol per dose. In cattle, we may use the sameconcentration, and increase the quantity of composition administered perdose.

The amount of thyroid-depressing agent used depends upon thephysiological effect desired both per se and in relationship to theeffect of the lipogenic agent used. Using tapazole in combination withdiethylstilbestrol as an example, we preferably use about 2 mg. to about7 mg. of tapazole in a composition containing from 5 mg. to 15 mg. ofdiethylstilbestrol, and most preferably, we use a composition containingabout 3 mg. of tapazole and about 10 mg. of diethylstilbestrol perchicken dose.

I Other thyroid-depressing agents and other lipogenic agents may be usedin amounts effectively corresponding to the amounts set forth above fortapazole and diethylstilbestrol. For example, propylthiouracil issubstantially less active per mg. than tapazole, and hence it requiresabout 25 mg. of propylthiouracil to produce the equivalent effect of 3mg. of tapazole, and we have used compositions containing 25 mg. ofpropylthiouracil and 15 mg. of diethylstilbestrol per injection dose inchickens.

We have found that the use of the composition containing a lipogenicagent and a thyroid-depressing agent in combination gives substantiallyimproved results in meat production. While we are not sure of themechanism by which this improvement is obtained, we believe that thethyroid-depressing agent lowers the metabolic rate of the physiologicalprocesses of the animal, and both tend to cause a greater production offibrous meat tissue, and facilitates the fat production and dispositionwhich results from the presence of lipogenic agent. There is thus apronounced co-operative or synergistic action bQ'. tween the two agents,and the results with a combination of the two agents substantiallysurpass the results obtained with either agent alone, and indeedsubstantially surpass the results which might be expected from theseparate actions of the two agents.

The following examples illustrate the invention and indicate theimproved results obtained by administration of the injectablecomposition prepared in accordance with our invention.

EXAMPLE 1 Four compositions were prepared, using the same vehicle ineach case and using ditferent quantities and proportions of tapazole anddiethylstilbestrol.

In each case, the vehicle consisted of a semi-solid plastic mixture of40 parts of polymerized polyethylene glycols having an averagemolecular-weight of 4000 and obtained commercially on the market asCarbowax 4000 and parts of polymerized polyethylene glycols having anaverage molecular-weight of 200, as a plasticizer. Each composition wasprepared by melting the vehicle at a temperature of about 85 F., andthoroughly mixing with the hot liquid vehicle an appropriate proportionof tapazole and diethylstilbestrol to give the desired concentration.The hot mixture was then brought to room temperature and filled intorubber-stoppered ampoules, so that the composition was suitable foradministration by extrusion injection with a dispensing gun as shown inour Patent No. 2,624,338. The four compositions were administered tofour groups of chickens, and a fifth group of chickens was maintained asa control. The compositions used were as follows:

Composition A contained 3 mg. of tapazole and 15 mg. ofdiethylstilbestrol in each 0.226 cc. dose of total composition.

Composition B contained 5 mg. of tapazole and 15 mg. ofdiethylstilbestrol in each 0.226 cc. dose of total composition.

Composition C contained no tapazole and 15 mg. of

diethylstilbestrol in each 0.226 cc. dose of total composition, and thuscorresponded to a commercial product which has been extensively used andsold under an active application to the Federal Food and DrugAdministration.

Composition D contained 3 mg. of tapazole and no diethylstilbestrol ineach 0.226 cc. dose of total composition.

chickens were killed; four weeks after the administration of thecompositions, and were dressed for market.

The results ofthe test were as follows:

Table l- Group 1 2 3 4 5' Oompos1tion-. {A B C 1 D. (Control)AmountTa'pazole mg. 3 5 3 Amount Diethylstilbestrol mg 15 15 Avg.beginning live wt. (lbs 1. 88 1. 80 1. 92 1. 85 2. 00 Avg. finish livewt. (lbs). 3. 98 3. 75 4. 02 3. 75 3. 77 Avg.wt. gain (lbs.) 2.10 1.952. 10 1.90 1.77 Avg;- percent wt. galn 112 108 109 103 88 Avg. feedconsumed per bird 6. 00 6. 49 7. 14 5. 78 6. 38 Feed conversion, lbs.feed per lb.

ga 2.86 3. 33 3.40 3.04 3. 60 Avg. dressed wt. (1b.) 2. 62 2. 51 2. 702. 41 2. 68 Percent dressed wt./startlng wt 139 139 140 127 129 Whereasthe controls gamed only 88% with a feed- .conversion ratio of 3.60pounds of feed per pound of gain, tapazole alone increased the gain to103% and reduced the feed-conversion ratio to 3.04. Diethylstilbestrolalone increased the gain to 109% but required a feed-conversion ratio of3.40.

Composition B gave a high weight gain, required a reducedfeed-conversion ratio, and gave a high dressed weight percentage.

Composition A increased the weight gain to 112%, reduced the feedconversion ratio to 2.86, and gave a high dressed weight percentage.

The chickens treated with Compositions A and B were best in quality.Those treated with Composition A were all of Grade A quality, whereasthe controls were all of lower quality. Those treated with CompositionC, which made a high weight gain on a high feed-conversion ratio, wereexcessively fat and averaged lower than Grade A for that reason.

EXAMPLE 2.

A composition containing 2 mg. of tapazole and 10 mg. ofdiethylstilbestrol per dose, prepared as in Example 1, was administeredto a group of 371 Beltville turkeys, and a comparable group of 373turkeys were kept under the same conditions as a control group. Theturkeys were about six weeks old when the test started, and were dressedand marketed four weeks later. Feed and weight data was kept by theproducer, and the dressed turkeys were graded by the purchasing produceThe treated birds required 0.4 pound less feed per pound of weight gainthan did the control birds. The treated turkeys thus had a higher weightgain (36% vs. 28%), required less feed per pound of gain, lost less indressing, and were of higher quality than the control group. Because ofthe difference in dressing yield and grade yield, the producer receiveda higher price for the treated turkeys, equivalent to 3 per pound offinished live weight.

EXAMPLE 3 In beef cattle and sheep, administration of compositions, suchas Composition D of Example 1 containing tapazole alone, and CompositionA of Example 1 containing tapazole and diethylstilbestrol in the ratioof 3 mg. tapazole. to. 15 mg, of. diethylstilbestrol, produce results.In such, ammals, the. administration is conveniently. made by extrusioninjection subcutaneously in the fleshy part of the ear., Conveniently,the compositions used are the same as set forth in Example 1 but. largeramounts are used. Thus, in lambs, the amount of suchcompositions.administered, can beabout. 0.45: cc., and in beef can beabout 0.45 cc. to 0.68 cc., and such dosages can be administered withthe standard extrusion-injection gun of-our'Patent No. 2,624,338, byactuating it two. or three times for each injection. Administration ofComposition A of Example 1 is especially advantageous. In beef, forexample, itnot only increases the weight" gain and lowers thefeed-conversion ratio, but increases the desired marbling of the meat,in which fat is deposited throughout the fibers of the meat.

While we do not fully understand the mechanism by which the agents usedare effective, our experience indicates that the estrogenic materialcauses an increased production of fat. With an estrogen alone, the fatis in part distributed in the meat, and in part tends to occur in fattylayers beneath the skin, especially in the lower parts of the animalbody. Our experience indicates that the thyroid-depressing agent exertsa controlling effect, which reduces the amount of feed consumed and bothcauses an increase in meat tissue production and causes the fat producedto be more firm and to be deposited in greater proportion throughout thetissue and less as fatty deposits beneath the skin.

We claim as our invention:

1. A composition for administration to meat-producing animals to promotemeat production thereby, comprising a relatively water-soluble estrogenand l-methyl-2-mercaptoimidazole in a non-toxic injectable carrier whichupon injection deposits the estrogen in solid state for absorption overa prolonged period and from which the 1-methyl-2-mercaptoimidazole ispromptly absorbed by body fluids.

2. A composition for administration to meat-producing animals to promotemeat production thereby, comprising a plastic, semi-solid mixturecontaining a relatively water-insoluble estrogen and1-methyl-2-mercaptoimidazole uniformly distributed in a water-solublevehicle comprising normally solid polyethylene glycols having an averagemolecular weight of at least 4000 and a polyhydric alcohol plasticizer.

3. A composition for administration to meat-producing animals to promotemeat production thereby, comprising a plastic semi-solid mixturecontaining 1-methyl-2-mercaptoimidazole and a relatively water-insolubleestrogen uniformly distributed in a water-soluble vehicle comprising amixture of polyethylene glycols having an average molecular weight of atleast about 4000 and polyethylene glycols having an average molecularweight of from about 200 to about 300.

4. A composition for injection administration to meatproducing animalsto promote meat-production thereby, comprising1-methyl-2-mercaptoimidazole and diethylstilbestrol in a non-toxicwater-soluble injectable vehicle.

5. A composition for injection administration to meatproducing animalsto promote meat-production thereby, comprising1-methyl-2-mercaptoimidazole and diethylstilbestrol in a non-toxicwater-soluble injectable vehicle, with the 1-methyl-2-rnercaptoimidazolepresent in smaller amount than the diethylstilbestrol.

6. The method of promoting meat production in meatproducing animals,which comprises administering beneath the skin of the animal a depositof diethylstilbestrol to be absorbed over a prolonged period oftreatment, and administering at the beginning of such period aninjection of l-methyl-Z-mercaptoimidazole.

7. The method of improving the promotion of meatproduction obtained bytreating meat-producing animals over a prolonged period withdiethylstilbestrol, which "7 v s 'oomprises administering to the animalsat the beginning OTHER REFERENCES of the treatment Peri an mjcctmn ofHormonal Relationships and Applications in the Procaptoimidazole, saidinjection when the animals are fowl duction f Meats, Milk and Eggs, pubL255, N fcomprising about 2 mg. to about 7 mg. of l-methyl-Z- councilMarch 1953, 5 7 99 2 mcrcaptoimidalole- 5 Stadelman: Poultry Sci., vol.30, No. 6, November 1951, p. 931. Cited Robblee: Poultry Sci., vol. 30,No. 5, pp. 712-774. UNITED STATES PATENTS Drug and Cos. Ind., vol. 70,No. 4, April 1952, p. 527.

' 2,681,297 Moore et al June 15, 1954 10 FOREIGN PATENTS 636,908 GreatBritain May 10, 1950 UNITED STATES PATENT OFFICE CERTIFICATE OFCORRECTION Patent No, 2,88l ll2 April '7, 1959 William Earl Mattox etal6 It is hereby certified that error appears in the printedspecification of the above numbered patent requiring correction and thatthe said Letters Patent should read as corrected below.

Column 2, line '35, for 'on the market as "'tapazole," read m on themarket under the registered trademark TAPAZOLE. in all other occurrencesof the Word, for "tapazole", including column .3, lines 69, 71, '73, andcolumn 4, lines 2, 4 6, 32, 42, 52, 55, 58, 64, and column 5 lines 2O;r39, '74, '75, and. column 6, line 1, read me methimazola column 5, line9, illable I, second data line, for "Tapazole" read methimazole column6, line 33, for Watersoluble" read e: water insoluble e l,

Signed and sealed this 4th day of August 195% SEAL) Attest:

KARL Ho AXLINE ROBERT C. WATSON Attesting Officer Commissioner ofPatents

1. A COMPOSITION FOR ADMINISTRATION TO MEAT-PRODUCING ANIMALS TO PROMOTEMEAT PRODUCTION THEREBY, COMPRISING A RELATIVELY WATER-SOLUBLE ESTROGENAND 1-METHYL-2-MERCAPTOIMIDAZOLE IN A NON-TOXIC INJECTABLE CARRIER WHICHUPON INJECTION DEPOSITS THE ESTROGEN IN SOLID STATE FOR ADSORPTION OVERA PROLONGED PERIOD AND FORM WHICH THE 1-METHYL-2-MERCAPTOIMIDAZOLE ISPROMPTLY ADSORBED BY BODY FLUIDS.